WO 97/06802 (Zeneca Limited) describe a series of pyridyl and pyrimidyl derivatives as oxido-squalene cyclase inhibitors which are claimed to lower blood cholesterol. WO 02/76925 (Eli Lilly), WO 03/004480, WO 03/024928 and WO 03/024929 (all Novo Nordisk A/S and Boehringer Ingelheim International) describe a series of substituted piperidines or piperazines which are claimed to bind selectively to the histamine H3 receptor. WO 03/62234 (Yamanouchi Pharmaceutical Co) describe a series of quinoxaline derivatives as poly(ADP-ribose) polymerase inhibitors. US2002115854 (Bristol Myers Squibb) describe a series of heterocyclic compounds as thrombin or factor Xa inhibitors. WO 97/23462 (Pfizer Inc) describe a series of quinoline and quinoxaline derivatives for treating a range of indications including benign prostatic hyperplasia, hypertension and hyperlipidaemia. WO 96/10022 (Zeneca Ltd) describe a series of heterocyclic compounds containing amino-aza-cyclyl and aryl groups as factor Xa protease and blood coagulation inhibitors. WO 03/103669 and WO 03/088967 (both Schering Corp) describe a series of piperidinyl benzimidazolone compounds as histamine H3 antagonists. WO 02/32893 and WO 02/72570 (both Schering Corp) describe a series of non-imidazole compounds as histamine H3 antagonists.
The histamine H3 receptor is predominantly expressed in the mammalian central nervous system (CNS), with minimal expression in peripheral tissues except on some sympathetic nerves (Leurs et al., (1998), Trends Pharmacol. Sci. 19, 177-183). Activation of H3 receptors by selective agonists or histamine results in the inhibition of neurotransmitter release from a variety of different nerve populations, including histaminergic and cholinergic neurons (Schlicker et al., (1994), Fundam. Clin. Pharmacol. 8, 128-137). Additionally, in vitro and in vivo studies have shown that H3 antagonists can facilitate neurotransmitter release in brain areas such as the cerebral cortex and hippocampus, relevant to cognition (Onodera et al., (1998), In: The Histamine H3 receptor, ed Leurs and Timmerman, pp 255-267, Elsevier Science B. V.). Moreover, a number of reports in the literature have demonstrated the cognitive enhancing properties of H3 antagonists (e.g. thioperamide, clobenpropit, ciproxifan and GT-2331) in rodent models including the five choice task, object recognition, elevated plus maze, acquisition of novel task and passive avoidance (Giovanni et al., (1999), Behav. Brain Res. 104, 147-155). These data suggest that novel H3 antagonists and/or inverse agonists such as the current series could be useful for the treatment of cognitive impairments in neurological diseases such as Alzheimer's disease and related neurodegenerative disorders.